A growing body of evidence suggests that brain-acting compounds, such as neurosteroids (e.g., androgens, progestins) or neurotransmitters (e.g., dopamine, derived from 3,4-dihydroxyphenylalanine (L-DOPA, or levodopa), serotonin, epinephrin, norepinephrine), have a modulatory role in the regulation of disorders influenced by receptors in the brain, such as depression, Parkinson's disease, Alzheimer's, psychiatric disorders and even loss of libido and aggression.
Neurosteroids act as modulators, either as stimulators or inhibitors, of several neurotransmitters. Neurotransmitters are chemicals that relay, amplify and modulate electrical signals between a neuron and another cell. Some neurotransmitters are excitatory, while others are primarily inhibitory. In many cases, as with dopamine, it is the function of the receptor which determines whether the transmitter is excitatory or inhibitory.
The brain floats in about 150 ml of cerebrospinal fluid (CSF), which slowly circulates down through the four ventricles, up through the subarachnoid space and exits into the cerebral veins through the arachnoid vili. Since the brain has no lymphatic system, the CSF serves as a partial substitute. While the brain and CSF are separated by the somewhat permeable pia mater, the blood-cerebrospinal fluid barrier and the blood-brain barrier (BBB) represent substantial protection against undesirable blood substances.
The BBB creates a protected chemical environment wherein certain molecules are able to perform functions independent of the functions those molecules may perform elsewhere in the body. One example of such a molecule is the neurotransmitter dopamine. When applied as an infusion, dopamine may be used for the treatment of heart attacks or kidney failure, but this mode of administration of dopamine is not suitable for the treatment of neurological disorders, such as Parkinson's disease.
L-DOPA is typically used to increase dopamine levels in the brain for the treatment of Parkinson's disease and Dopa-Responsive deficiencies because it is able to cross the blood-brain barrier, whereas dopamine itself cannot. Once L-DOPA has entered the central nervous system (CNS), it is metabolized to dopamine by aromatic L-amino acid decarboxylase.
Often, during treatment of neurological diseases such as Parkinson's Disease, L-DOPA is administered to patients together with other compounds, including carbidopa, benserazide, and Entacapone/tolcapone. Further, other drugs or complimentary therapies may be administered to Parkinson's patients in concert with L-DOPA treatment, including dopamine agonists, MAO-B inhibitors, glial-derived neurotropic factor for gene therapy, and several neuroprotective agents.
To increase the efficacy of medicinal treatments of CNS disorders, delivery of molecules to the brain via delivery to the nasal cavity has been investigated. The inventors have recently provided evidence in Banks, et al. (J Drug Target. 2009 February; 17(2):91-7), incorporated herein by reference, that intranasal administration of testosterone is able to target the brain, and in particular, is able to target the olfactory bulb, hypothalamus, striatum, and hippocampus. Drug delivery to the brain via the nasal cavity potentially offers many advantages that include direct access to the brain, rapid adsorption into the nasal mucosa due to the abundant presence of capillary vessels in the nose, rapid onset of action, avoidance of hepatic first-pass metabolism, utility for chronic medication, and ease of administration. However, still little is known on factors controlling the nasal delivery of drugs to the brain. A drug can reach the brain by different ways, including olfactory neuronal pathway, extraneuronal olfactory epithelial pathway, trigeminal nerve pathway, systemic pathway. It is also possible that more of the aforementioned pathways may contribute to the delivery of the molecule to the brain. Once a drug is in the brain, it's amount can be further influenced by BBB efflux transporter systems.
Thus, there has been a long-felt need in the art for investigations into and the generation of formulations that facilitate molecular uptake into the tissue of the nasal cavity, thereby increasing the concentration of the drug in brain tissue.
However, maintaining clinically effective drug concentrations in vivo, particularly in brain tissue, has been a challenge. The time period during which molecules may become absorbed is reduced as a result of the rapid mucociliary clearance of a therapeutic agent from the site of deposition and the presence of enzymes in the nasal cavity, which that may cause degradation of the therapeutic agent.
Many efforts have been made in the art in attempt to overcome these limitations.
GB 1987000012176 relates to the use of bioadhesive microspheres to increase the length of time that molecules reside in the nasal cavity. It has also been found that the use of enhancers and stabilizers improves permeability of the nasal membrane and prevents drug degradation, respectively. PCT/GB98/01147 (U.S. Pat. No. 6,432,440) pertains to the use of in situ gelling pectin formulations for drug delivery.
Bayne, U.S. Reissue Pat. No. RE29,892 pertains to a method of increasing the dopamine concentration in brain tissue through administration of a composition comprising dopamine and a hydrazine compound. The method allows for administration of the composition topically, rectally, orally, or parenterally. Preferred compositions include hydrazine compounds such as L-α-hydrazino-α-lower alkyl-3,4-dihydroxyphenyl propionic acid and L-DOPA and its pharmaceutically accepted salts.
Haffner et al., U.S. Pat. No. 4,826,852, relates to the treatment of psychoses such as schizophrenia and discloses methods of administrating ergolinyl compounds to increase dopamine concentrations in mammalian brain tissue.
Additionally, Wenzel et al., U.S. Pat. No. 5,624,960, pertains to the treatment of Parkinson's disease through the oral administration of a composition containing levodopa and carbidopa (MK-486). Further, Mandel et al., U.S. Pat. No. 6,319,905, relates to the tightly modulated production of L-DOPA in the mammalian brain by gene therapy. In Mendel et al., modulators such as tetrahydropterin (PH4) are used to control the generation of dopamine.
Despite the latter attempts to develop an effective nasal delivery system, there remains a need in the art to identify a formulation that, inter alia, limits the rate of mucociliary clearance and degradation of molecules in the nasal cavity, thereby increasing the brain's availability to such molecules, particularly neurotransmitters. Preferably, the formulation should have physical and chemical properties that facilitates brain uptake of molecules/drugs, such as dopamine. The identification of a formulation that may increase the bioavailability of neurotransmitters to brain tissue would provide much-needed treatment options for diseases associated with, for example, dopamine or serotonin deficiency in the brain, including depression, Parkinson's disease, attention deficit hyperactivity disorder (ADHD), addiction to drugs and alcohol, and various psychiatric disorders.
Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.